Transferrin (rs3811647) gene polymorphism in iron deficiency anemia
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ABSTRACT:
SUBMITTER: Manjari K
PROVIDER: S-EPMC4044269 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population.
| S-EPMC8836508 | biostudies-literature
Project description:Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach.
| S-EPMC3669438 | biostudies-literature
Project description:Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the "atypical" microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field.
| S-EPMC4439901 | biostudies-literature
Project description:It has been previously suggested that large amounts of oxalate in plasma could play a role in autism by binding to the bilobal iron transport protein transferrin (hTF), thereby interfering with iron metabolism by inhibiting the delivery of iron to cells. By examining the effect of the substitution of oxalate for the physiologically utilized synergistic carbonate anion in each lobe of hTF, we sought to provide a molecular basis for or against such a role. Our work clearly shows both qualitatively (6 M urea gels) and quantitatively (kinetic analysis by stopped-flow spectrofluorimetry) that the presence of oxalate in place of carbonate in each binding site of hTF does indeed greatly interfere with the removal of iron from each lobe (in the absence and presence of the specific hTF receptor). However, we also clearly demonstrate that once the iron is bound within each lobe of hTF, neither anion can displace the other. Additionally, as verified by urea gels and electrospray mass spectrometry, formation of completely homogeneous hTF-anion complexes requires that all iron must first be removed and hTF then reloaded with iron in the presence of either carbonate or oxalate. Significantly, experiments described here show that carbonate is the preferred binding partner; i.e., even if an equal amount of each anion is available during the iron loading process, the hTF-carbonate complex is formed.
| S-EPMC3887466 | biostudies-literature
Project description:AimWe analyzed the added value of sTfR measurement in routine clinical practice to standard parameters (SP) of iron deficiency in the detection of iron deficiency anemia (IDA) in patients with rheumatoid arthritis (RA).MethodsBlood samples from 116 patients with RA were analyzed in a prospective study. Based on biochemical parameters, patients were classified as having IDA, anemia of chronic disease (ACD), IDA with concomitant ACD (ACD/IDA), or "other anemia." Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of sTfR and SP of iron status alone and in combination were calculated for the diagnosis of IDA in general, i.e., IDA or ACD/IDA.ResultsIn the whole sample, with regard to the diagnosis of iron deficiency (IDA or ACD/IDA), sTfR had a higher sensitivity compared both to the combined use of SP and to the combination of SP with sTfR (80.9% versus 66.7/54.8%). Specificity, PPV and NPV did not differ substantially. When patients were stratified in groups with high (CRP levels above the median, i.e., 24.1 mg/l) and low (CRP levels less or equal to the median) inflammation, the diagnostic superiority of sTfR was restricted to patients with high inflammation. In this group, the diagnostic performance of sTfR was superior both to the combined use of SP and the combination of SP with sTfR with higher sensitivity (100% versus 52.4%) and NPV (100% versus 77.7/76.7%) and comparable specificity and PPV.ConclusionFor the detection of iron depletion (IDA or ACD/IDA) in anemic RA patients, sTfR is superior to SP of iron deficiency only in highly inflammatory states.
| S-EPMC9581666 | biostudies-literature
Project description:BackgroundGenome-wide-association studies have identified the TMPRSS6 polymorphism rs855791 has the strongest association with red blood cell indices or iron parameters in general population. Whether this genetic variant influences the susceptibility of iron deficiency anemia (IDA) in women with menstruation has not been well studied.MethodsIn this case-control study, we enrolled 67 women with IDA and 107 healthy volunteers, and analyzed their complete blood counts, rs855791 genotypes, and menstrual amounts. Menstrual blood loss was evaluated with a pictorial blood-loss assessment chart.ResultsThere were significantly fewer rs855791 C homozygotes in the IDA group than in the healthy group (11.9% vs. 25.2%, p = 0.03). The odds ratio (OR) of C homozygotes having IDA versus non-CC subjects having IDA was 0.4 (95% CI, 0.17 - 0.95, p = 0.04). When the analysis was confined to study subjects with menorrhagia, this difference became more prominent (9.6% vs. 28.6%, p = 0.01; OR, 0.27, 95% CI, 0.09 - 0.77, p = 0.01). For women with non-CC genotypes, there was an inverse correlation between hemoglobin levels and menstrual loss (p < 0.001); however, this association was not found for those with genotypes CC (p = 0.15).ConclusionsOur study suggests homozygosity for TMPRSS6 rs855791 C genotype has a protective role against IDA in women at reproductive age, especially in those with menorrhagia.
| S-EPMC4003547 | biostudies-literature
Project description:Purpose: The goal of this study was to probe for the effects of iron-deficiency anemia on the cardiac transciprtome using RNA-seq Methods: C57B6 mice were weaned onto a control or iron-deficient diet for 6 weeks. Hearts were removed and total mRNA was submitted for RNA-seq. Sequencing data was aligned using STAR and differetial gene expression analysis conducted in R using EdgeR and DESeq2. qRT–PCR validation for genes of interest was performed using TaqMan and SYBR Green assays. Results: We mapped about 24 million sequence reads per sample to the mouse genome (build mm10) and identified 13,590 transcripts in the hearts of control and iron-deficient mice after removing lowly expressed genes and PCR duplicates. Differential gene expression analysis showed approximately 78% downregulated and 22% upregulated genes in iron-deficiency anemia compared to controls. PCA plot showed control and iron-deficient hearts clustering in two distinct and separate clusters. Conclusions: Our study represents the first whole-transcriptomic study on cardiac samples obtained from iron-deficient and anemic mice, with biologic replicates, generated by RNA-seq technology. The RNA-seq data presented here can be used by others to explore which pathways are affected by iron-deficiency anemia
2020-12-03 | GSE162493 | GEO
Project description:Iron deficiency contributes to anemia after transplantation. The magnitude of iron loss from blood loss in the peri-transplantation period has not been quantified. We prospectively estimated phlebotomy and surgical losses over the first 12-weeks following transplantation in 39 consecutive renal transplant recipients on hemodialysis (HD), peritoneal dialysis (PD), or chronic kidney disease (CKD). At transplant, ferritin levels were <200 ng/ml in 51% of the patients, and iron saturation was </=20% in 44%. CKD patients more commonly had ferritin levels <200 ng/ml than either HD or PD patients (100% vs. 21% vs. 67%, P < 0.0002, respectively). Blood loss was similar among HD, PD and CKD patients (833 +/- 194 vs. 861 +/- 324 vs. 755 +/- 79 ml respectively, P = NS), and no difference between deceased and living donor transplant recipients (881 +/- 291 vs. 788 +/- 162 ml, P = 0.33). Based on baseline hemoglobin (Hgb) of 11.8 g/dl, we estimated that an additional 330 mg of iron was needed to normalize hemoglobin to 13 g/dl, and 605 mg to increase hemoglobin to 14 g/dl. Blood and iron losses over the first 12 weeks post-transplant are substantial and may warrant early administration of intravenous iron.
| S-EPMC2754723 | biostudies-literature
Project description:PurposeWhether anemia type modifies the risk of pregnancy and newborn outcomes and the effectiveness of iron supplementation is unclear. We examined the association of iron deficiency anemia (IDA) and non-iron deficiency anemia (NIDA) on the risks of these outcomes and the extent to which anemia type modifies the impact of prenatal iron supplementation.MethodsThis was a secondary analysis of a placebo-controlled trial of iron supplementation among 1450 HIV-negative women in Tanzania. Eligibility criteria included gestational age < 27 weeks, hemoglobin > 85 g/L, and ferritin > 12 µg/L. Individuals were categorized as non-anemia, IDA or NIDA using hemoglobin, ferritin and CRP. Analyses were conducted using regression models and likelihood ratio tests.ResultsCompared to the non-anemia group, delivery hemoglobin was lower by 15 g/L (95% CI 10.9, 19.3) in the baseline IDA group, and 7.3 g/L (95% CI 3.1, 11.5) in the baseline NIDA group. The RRs of anemia severity, iron deficiency, placental malaria, stillbirths, perinatal mortality, birthweight, and preterm birth were not different among women in the baseline NIDA group (vs. non-anemia) compared to the baseline IDA group (vs. non-anemia). The difference in the mean delivery hemoglobin for iron supplementation and placebo arms was 8 g/L (95% CI 6, 11) in the non-anemia group, 7 g/L (95% CI 2, 13) in the NIDA group, and 16 g/L (95% CI 10, 22) in the IDA group.ConclusionIron supplementation is effective even among pregnant women with NIDA.Trial registrationNCT01119612 (May 7, 2010).
| S-EPMC9987582 | biostudies-literature
Project description:(1) Background: Anemia has comprehensive adverse effects on the growth and development of children. In this study, we analyzed the potential effects of different types of anemia on early-life neurobehavioral development. (2) Methods: A total of 2601 children aged 6-24 months, whose parents agreed to participate in this study, underwent routine blood tests and neurobehavioral development assessment. The children's parents or other primary caregivers were interviewed with a face-to-face questionnaire at the time of enrollment in the study. Anemia was determined by hemoglobin < 110 g/L and classified into iron-deficiency and non-iron-deficiency anemia according to the levels of serum ferritin, C-reactive protein, and alpha-1-acid glycoprotein. Neurobehavioral development was assessed by the China Developmental Scale for Children and divided into five domains: gross motor, fine movement, adaptability, language, and social behavior. The development quotient (DQ) was used to measure the level of total neurobehavioral development and each domain of neurobehavioral development. (3) Results: The prevalence of anemia in children aged 6-24 months was 26.45%, of which iron-deficiency anemia only accounted for 27.33%. Compared with children without anemia, those with iron-deficiency anemia had a significantly lower developmental quotient (DQ) for total neurobehavioral development and gross motor and adaptability development. The partial regression coefficients were -1.33 (95% CI -2.36, -0.29; p = 0.012), -1.88 (95% CI -3.74, -0.03; p = 0.047), and 1.48 (95% CI -2.92, -0.05; p = 0.042), respectively. Children with non-iron-deficiency anemia had significantly lower DQ for total neurobehavioral development and gross motor and fine movement development than those without anemia. The partial regression coefficients were -0.94 (95% CI -1.64, -0.25; p = 0.008), -1.25 (95% CI -2.48, -0.03; p = 0.044), and -1.18 (95% CI -2.15, -0.21; p = 0.017), respectively. There were no statistically significant differences in total neurobehavioral development and the five domains of neurobehavioral development between children with non-iron-deficiency and iron-deficiency anemia. The partial β values were 0.40 (95% CI -1.53, 2.33; p = 0.684), 0.21 (95% CI -1.39, 1.81; p = 0.795), 0.63 (95% CI -1.03, 2.28; p = 0.457), 0.16 (95% CI -1.78, 2.10; p = 0.871), 0.35 (95% CI -1.32, 2.01; p = 0.684), and 0.34 (95% CI -0.77, 1.46; p = 0.545), respectively. (4) Conclusions: Both iron-deficiency anemia and non-iron-deficiency anemia were negatively correlated with the neurobehavioral development of children. Negative correlations were found between iron-deficiency anemia and gross motor and adaptability development and between non-iron-deficiency anemia and gross motor and fine movement development.
| S-EPMC8537382 | biostudies-literature